Sunlight-induced skin cancer is the most prevalent cancer in the United States, and appropriate strategies to prevent this cancer would save lives and have significant social impact. In earlier studies, we found that oral administration of caffeine inhibited ultraviolet B light (UVB)-induced skin carcinogenesis in mice. Mechanistic studies indicated a stimulatory effect of caffeine administration on DVB-induced apoptosis in the epidermis and in tumors. Caffeine administration did not affect apoptosis in normal non-UVB irradiated mice or in non-tumor areas of tumor-bearing mice. In a recent studies we treated mice with oral administration of caffeine and found that this treatment with caffeine stimulated locomotor activity and decreased the thickness of dermal fat away from tumors and directly under tumors. An increase in locomotor activity by providing mice with the opportunity for voluntary running wheel exercise also decreased body fat and decreased the thickness of the dermal fat layer. More importantly, voluntary exercise inhibited UVB-induced skin carcinogenesis in mice. This was the first demonstration of skin cancer inhibition by voluntary exercise. We plan to determine the effects of voluntary running wheel exercise on UVB-induced apoptosis and cell proliferation in the epidermis of SKH-1 mice. We will investigate the possible synergistic inhibitory effects of voluntary running wheel exercise in combination with oral administration of caffeine on the formation of nonmalignant and malignant skin tumors in SKH-1 'high risk' mice previously treated chronically with UVB. We will determine the possible synergistic effects of voluntary running wheel exercise in combination with oral administration of caffeine on the levels of apoptosis and cell proliferation in histologically-characterized UVB-induced tumors and in areas of the epidermis away from tumors. The tissue fat levels in these mice will be determined and the relationship between the fat level and the expression of apoptosis and cell proliferation will be analyzed. The proposed studies will provide a better understanding of the mechanisms of cancer prevention by voluntary exercise alone and in combination with caffeine, and these studies may help in the development of a diet/exercise program to prevent cancer [unreadable] [unreadable] [unreadable]